process of approval of pes-
ticides in the EU.
“
velopment), there is not always agreement among scientists that such tests accurately identify risks. For example, in an evaluation of a guideline for de- velopmental neurotoxicity67 (i.e. effects of chemi-
cals on the development of the offspring’s neural system during pregnancy or childhood), 16 stud- ies of five evaluated chemicals have been summa- rized68. Of these, five studies were performed ac-
cording to the OECD guideline TG 426, all but one found no sign of developmental neurotoxic- ity. In contrast, of the eleven studies not performed according to the guideline, all found evidence of developmental neurotoxicity. A more recent and extensive survey of studies investigating the poten- tial developmental neurotoxicity of the compound Bisphenol A (BPA) suggests that studies performed according to guideline TG 426 may overlook sen- sitive effects of BPA, especially in female offspring. Especially anxiety-related, social and sexual behav- iours, which are not tested according to TG 426, were found to be affected by BPA exposure during development69. One example of potential develop-
mental neurotoxicity (chlorpyrifos) is discussed in some detail below, in section “In-depth example: Developmental neurotoxic effects of chlorpyrifos”.
Cumulative effects
Another weakness is that (with few exceptions for chemically closely related compounds) the cur- rent risk assessment considers only one pesticide at a time, in spite of the obvious fact that we all are constantly exposed to a large number of pesti- cides simultaneously via our food. The reasons are (1) methodological difficulties in estimating the ef- fects of exposure to multiple compounds, and (2) companies have the right to have their product as- sessed on its own merits, i.e. independent of which products their competitors sell.
Effects of several pesticides may add up to adverse effects. In animal studies, cases are known where mixtures of pesticide cause adverse effects at dose levels where the individual pesticides show no ef- fect70, 71 (so-called cumulative effects).
Independent science is disregarded
One weak point of the regulatory process of pes- ticide approval is the fact that independent science has a low impact on this process. Since Regulation
1107/200961 came into effect, independent science
must be considered in the process of pesticide ap- proval. However, an EFSA guidance document72
effectively assigns independent studies a low im- pact, and in consequence, independent science is generally disregarded73. For example, of the hun-
dreds of epidemiological studies of pesticide effects exposure on human health (discussed in chapter “Public health effects of low-level pesticide expo- sure” below), to our knowledge not a single one has been considered valid when setting toxicologi- cal reference values in EFSAs risk assessment in the approval process of pesticides.
Of course, epidemiological studies are not gener- ally designed for the purpose of regulatory risk assessment. For example, epidemiological studies generally cover “real-life” situations with a co- exposure to various pesticides and other chemi- cals, and may assess exposure to single compounds, groups of pesticides, or overall pesticide expo- sure. In contrast, in regulatory risk assessment, all animal studies are performed using the individual compound, without consideration of mixed expo- sures. Nonetheless, the fact that no epidemiologi- cal study is regarded relevant for the regulatory risk assessment might indicate that systematic barriers exist against the inclusion of such studies, and puts focus on the question whether current regulatory risk assessment indeed uses all available knowledge. It should be mentioned that the approval process is intended not only to protect the environment and consumers from negative pesticide effects, but also farm workers. In many epidemiological studies, ef- fects on farm workers are addressed. One example of what this can mean in practice is discussed in detail below, in section “In-depth example: Devel- opmental neurotoxic effects of chlorpyrifos”. Another issue is that the studies submitted by the industry to EFSA are generally “protected” (not available for the public or for researchers).
Also, for some of the chronic diseases that have in- creased during recent decades in many countries, the mechanisms of disease onset are still unknown. This applies for example to allergies, Alzheimer’s disease, type 2 diabetes, obesity, decreasing fertility, ADHD. Many of these diseases have been linked to expo-
Ph O TO : IST OCKP h O TO © COURT yARDPI x
sure to endocrine disrupting compounds in animal and human studies74. Lacking knowledge of the bio-
chemical and physiological mechanisms, it is in some cases difficult or impossible to develop adequate tests that demonstrate the safety of active substances. Furthermore, all toxicological risk assessment is based on extrapolations (with safety margins) from animal studies, and there is normally no direct knowledge of effects in humans. Direct toxicological tests in hu- mans would be unethical. However, the structured collection of reported adverse effects after market release (e.g. from farmers) and the conducting of epi- demiological studies (in farmers and consumers) are examples of viable approaches to measuring some potential “real-life” adverse effects in humans. Today, no such effort of validating the findings of the risk assessment after market release is done or required by the regulatory authorities.
There is substantially more focus on the active sub- stance than on its metabolites in the safety assess- ment of pesticides. For example, the approval of the fungicide carbendazim has expired in the EU (in november 2014) without a chance of re-approval, because carbendazim is now classified in mutagen- icity category 1B (“Substances to be regarded as if they induce heritable mutations in the germ cells of humans”), and therefore the cut-off criterion
for mutagenicity (see section “Basics of regulation in the EU” above) applies.
The fungicide thiophanate-methyl forms carben- dazim as a metabolite both in the field and after ingestion by mammals. The cut-off criterion for mutagenicity does, however, not directly apply for thiophanate-methyl, as it only applies for ac- tive substances, safeners, and synergists, but not for metabolites.
Another issue is that the EU member states have the possibility of temporarily authorizing the mar- keting of banned pesticides. This possibility was originally intended as an emergency response (to tackle dangers (e.g. outbreaks of plant diseases and insects) that could not be dealt with by other rea- sonable means), but has been used frequently. For example, in 2011, 230 such “derogations” were is- sued by the EU member states75.